The invention relates to a combination comprising mirtazapine, to a package containing dosage units comprising mirtazapine, and to a method of treatment of depression and related disorders.
Disorders of the central nervous system, such as depression and anxiety are illnesses that affect people of all ages. Although there are many effective drugs available for treatment of these diseases, the currently available methods of treatment are often still not adequate. Most noteworthy is that there are no positive treatment results in about one third of all subjects with depression or anxiety and recovery in the effectively treated group is slow, with an onset of effect at the earliest two weeks after the start of drug treatment.
Mirtazapine (Org 3770; disclosed in U.S. Pat. No. 4,062,848), or the newly introduced drug gepirone (disclosed in U.S. Pat. No. 4,423,049), are examples of modern drugs for the treatments of depression and anxiety with favourable side effect profiles and very low risks for a lethal overdose. For more effective treatment there is hope that the different mechanisms of action of drugs enables complementary use, in the sense that patients not responding to one drug, may turn out to be responsive to another drug. Sometimes, drugs with the same therapeutic indication are prescribed as combination therapy in order to profit from such a mutually supplementary effect although it is generally not recommended to combine antidepressant drugs in view of risks for cumulative side effects or synergistic toxic interactions (Schweitzer and Tuckwell, in Drug Safety, Vol. 19, pp 455-464, 1998). Usually, if a seemingly positive effect of a known drug combination occurs in an individual patient, the positive effect is due to only one of the drugs in the combination. More desirable is a truly synergistic effect of two drugs with the same indication, in the sense that the effect of the combination is superior over an additive effect of the effects of both drugs in an individual patient. There are only very few synergistic therapeutic drug interactions known which have found acceptance in the area of treatment of central nervous system diseases. Most information is available on so-called augmentation therapy of treatment resistant depression by addition of lithium to anti-depressant drugs. The use of such a combination is viewed with caution in view of the side effects of lithium (Hardy et al., Journal Clin. Psychopharmacology, vol. 17, pp 22-26, 1997). The results of a combination of lithium with mirtazapine has been disclosed with favourable results, but the augmentation is not so strong that this combination would be selected as first choice treatment of depressive disorders (Bruijn et al., Journal Clin. Psychiatry, Vol. 59, pp 657-663, 1998).
It is therefore all the more surprising that a synergistic effect is found with mirtazapine and gepirone. This invention provides for a combination comprising an amount of mirtazapine, or a pharmaceutically acceptable salt or solvate thereof, and an amount of gepirone, or a pharmaceutically acceptable salt or solvate thereof, optionally in association with one or more pharmaceutically acceptable carriers, whereby the amount of gepirone and the amount of mirtazapine are such that the effect of the combination is more favourable than the added effects of the amounts of each drug separately. Thus, gepirone and mirtazapine truly have a synergistic interaction when used in the treatment of depression and related disorders. As a consequence, the combined use of mirtazapine and gepirone has better effects in more patients in comparison to each drug alone. The better effect can reside in less side effects or a faster or more complete recovery in individual patients or in the overall result of the treatment of a group of patients. The preferred use of the combination will be in the treatment of the before mentioned treatment-resistant depression, also known as refractory depression or treatment refractory depression.
The present invention thus concerns the administration of two different psychotropic drugs from different pharmacological categories, each drug enhancing the therapeutic efficacy of the other drug in the treatment of depression and related disorders.
The following specifications of the terms used above serve to clarify better what is provided by this invention.
The drug name mirtazapine also refers to the individual (R) and (S) enantiomers of mirtazapine. These can be used as their salts, substantially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer or as mixtures of such enantiomers in any proportions including racemic mixtures containing substantially equal amounts of the two enantiomers.
Unless otherwise stated all amounts of the active components refer to the weights of mirtazapine or gepirone as base. According to the terminology in this description the drugs gepirone and mirtazapine are the active ingredients or active components of the combination.
Pharmaceutically acceptable salts include acid addition salts, for example, hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation.
The terms pharmaceutically acceptable carriers and excipients refer to those substances known in the art to be allowable as filler or carrier material in pills, tablets, capsules etc. The substances are usually approved for this purpose by health-care authorities and are inactive as pharmacological agents. A compilation of pharmaceutically acceptable carriers and excipients can be found in the Handbook of Pharmaceutical excipients (2nd edition edited by A. Wade and P. J. Weller; Published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London in 1994). Specifically, lactose, starch, cellulose derivatives and the like, or mixtures thereof, can be used as carriers for the active components of the combination according to this invention.